The long-term goals of this proposal are to define mechanisms of regulation of hepatic lipase (HL) levels and to determine how genetic variation at the HL gene locus modulates these levels under a variety of physiological and pathological states. HL plays a key role in lipoprotein metabolism by catalyzing the hydrolysis of triglycerides and phospholipids. A high level of HL is associated with two important metabolic risk factors for atherosclerosis: diminished concentrations of plasma high density lipoprotein cholesterol (HDL-C) and an increased prevalence of small, dense low density lipoprotein (LDL) particles. A significant proportion (20-30%) of the total variability in HL activity is explained by the common genetic variation in the regulatory sequences of the HL gene whereby, the variant form was observed to be associated with lower HL and higher HDL2 levels. Gender is another modulating factor since women have, on average, higher levels of HDL2 and lower levels of HL. The underlying hypotheses of this proposal are, first, that one or more of the observed regulatory sequence variants causes diminished HL gene expression which, in turn, results in increased HDL-C levels and expression is regulated by cholesterol and estrogens. Our preliminary in vitro studies indicate that sterols up-regulate and estrogens down-regulate activity of the HL gene promoter, respectively. The specific aims are to: 1) Determine by association and linkage analysis whether the observed LIPC promoter variants underlie the observed interindividual variation in levels of hepatic lipase activity and HDL2 estrogens and sterols and assess the role of the regulatory sequence variants modulate the relationships between HL levels and gender, menopause status, estrogen replacement therapy and intra-abdominal fat deposits. The results of these studies will provide insights into the molecular genetic bases for interindividual variation in HL activity and the associated plasma lipoprotein profiles. This will open the door for novel pharmaceutical approaches that target modification of the lipoproteins.